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Annual Review of Genomics and Human Genetics

Volume 21, 2020

The Genetics of Epilepsy

Abstract

Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. Epilepsy may have discernible structural, infectious, metabolic, and immune etiologies; however, in most people with epilepsy, no obvious cause is identifiable. Based initially on family studies and later on advances in gene sequencing technologies and computational approaches, as well as the establishment of large collaborative initiatives, we now know that genetics plays a much greater role in epilepsy than was previously appreciated. Here, we review the progress in the field of epilepsy genetics and highlight molecular discoveries in the most important epilepsy groups, including those that have been long considered to have a nongenetic cause. We discuss where the field of epilepsy genetics is moving as it enters a new era in which the genetic architecture of common epilepsies is starting to be unraveled.

Keyword(s): epilepsy, epilepsy genes, genetics, genome-wide association study, GWAS, oligogenic models, polygenic risk scores, repeat expansions
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/content/journals/10.1146/annurev-genom-120219-074937
2020-08-31
2024-04-25
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Literature Cited

  1. 1. 
    Annegers JF, Hauser WA, Shirts SB, Kurland LT 1987. Factors prognostic of unprovoked seizures after febrile convulsions. N. Engl. J. Med. 316:493–98
     [Google Scholar]
  2. 2. 
    Arsov T, Mullen SA, Damiano JA, Lawrence KM, Huh LL et al. 2012. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia 53:e204–7
     [Google Scholar]
  3. 3. 
    Arsov T, Mullen SA, Rogers S, Phillips AM, Lawrence KM et al. 2012. Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann. Neurol. 72:807–15
     [Google Scholar]
  4. 4. 
    Bailey JN, de Nijs L, Bai D, Suzuki T, Miyamoto H et al. 2018. Variant intestinal-cell kinase in juvenile myoclonic epilepsy. N. Engl. J. Med. 378:1018–28
     [Google Scholar]
  5. 5. 
    Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH et al. 2019. The landscape of epilepsy-related GATOR1 variants. Genet. Med. 21:398–408
     [Google Scholar]
  6. 6. 
    Balestrini S, Milh M, Castiglioni C, Luthy K, Finelli MJ et al. 2016. TBC1D24 genotype-phenotype correlation: epilepsies and other neurologic features. Neurology 87:77–85
     [Google Scholar]
  7. 7. 
    Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR et al. 2012. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44:1255–59
     [Google Scholar]
  8. 8. 
    Baulac S. 2016. mTOR signaling pathway genes in focal epilepsies. Prog. Brain Res. 226:61–79
     [Google Scholar]
  9. 9. 
    Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH et al. 2010. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51:676–85
     [Google Scholar]
  10. 10. 
    Berkovic SF. 2008. Progressive myoclonus epilepsies. Epilepsy: A Comprehensive Textbook JJ Engel, TA Pedley 2525–35 Philadelphia: Lippincott Williams & Wilkins, 2nd ed..
     [Google Scholar]
  11. 11. 
    Berkovic SF, Howell RA, Hay DA, Hopper JL 1998. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann. Neurol. 43:435–45
     [Google Scholar]
  12. 12. 
    Berkovic SF, McIntosh A, Howell RA, Mitchell A, Sheffield LJ, Hopper JL 1996. Familial temporal lobe epilepsy: a common disorder identified in twins. Ann. Neurol. 40:227–35
     [Google Scholar]
  13. 13. 
    Burgess R, Wang S, McTague A, Boysen KE, Yang X et al. 2019. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann. Neurol. 86:821–31
     [Google Scholar]
  14. 14. 
    Campeau PM, Kasperaviciute D, Lu JT, Burrage LC, Kim C et al. 2014. The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol 13:44–58
     [Google Scholar]
  15. 15. 
    Carvill GL, Engel KL, Ramamurthy A, Cochran JN, Roovers J et al. 2018. Aberrant inclusion of a poison exon causes Dravet syndrome and related SCN1A-associated genetic epilepsies. Am. J. Hum. Genet. 103:1022–29
     [Google Scholar]
  16. 16. 
    Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ et al. 2013a. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet 45:825–30
     [Google Scholar]
  17. 17. 
    Carvill GL, Regan BM, Yendle SC, O'Roak BJ, Lozovaya N et al. 2013b. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat. Genet. 45:1073–76
     [Google Scholar]
  18. 18. 
    Cavalleri GL, Lynch JM, Depondt C, Burley MW, Wood NW et al. 2005. Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here. Brain 128:1832–40
     [Google Scholar]
  19. 19. 
    Cen Z, Jiang Z, Chen Y, Zheng X, Xie F et al. 2018. Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1. Brain 141:2280–88
     [Google Scholar]
  20. 20. 
    Christensen J, Pedersen MG, Pedersen CB, Sidenius P, Olsen J, Vestergaard M 2009. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet 373:1105–10
     [Google Scholar]
  21. 21. 
    Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P 2001. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68:1327–32
     [Google Scholar]
  22. 22. 
    Cooper MS, McIntosh A, Crompton DE, McMahon JM, Schneider A et al. 2016. Mortality in Dravet syndrome. Epilepsy Res 128:43–47
     [Google Scholar]
  23. 23. 
    Corbett MA, Bellows ST, Li M, Carroll R, Micallef S et al. 2016. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology 87:1975–84
     [Google Scholar]
  24. 24. 
    Corbett MA, Kroes T, Veneziano L, Bennett MF, Florian R et al. 2019. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat. Commun. 10:4920
     [Google Scholar]
  25. 25. 
    Corey LA, Berg K, Pellock JM, Solaas MH, Nance WE, DeLorenzo RJ 1991. The occurrence of epilepsy and febrile seizures in Virginian and Norwegian twins. Neurology 41:1433–36
     [Google Scholar]
  26. 26. 
    Corey LA, Pellock JM, Kjeldsen MJ, Nakken KO 2011. Importance of genetic factors in the occurrence of epilepsy syndrome type: a twin study. Epilepsy Res 97:103–11
     [Google Scholar]
  27. 27. 
    Cossette P, Liu L, Brisebois K, Dong H, Lortie A et al. 2002. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat. Genet. 31:184–89
     [Google Scholar]
  28. 28. 
    Curatolo P, Moavero R, de Vries PJ 2015. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 14:733–45
     [Google Scholar]
  29. 29. 
    Daber RD, Conlin LK, Leonard LD, Canevini MP, Vignoli A et al. 2012. Ring chromosome 20. Eur. J. Med. Genet. 55:381–87
     [Google Scholar]
  30. 30. 
    Dashnow H, Lek M, Phipson B, Halman A, Sadedin S et al. 2018. STRetch: detecting and discovering pathogenic short tandem repeat expansions. Genome Biol 19:121
     [Google Scholar]
  31. 31. 
    Davies NM, Holmes MV, Davey Smith G 2018. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362:k601
     [Google Scholar]
  32. 32. 
    Dazzo E, Fanciulli M, Serioli E, Minervini G, Pulitano P et al. 2015. Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. Am. J. Hum. Genet. 96:992–1000
     [Google Scholar]
  33. 33. 
    Dazzo E, Rehberg K, Michelucci R, Passarelli D, Boniver C et al. 2018. Mutations in MICAL-1 cause autosomal-dominant lateral temporal epilepsy. Ann. Neurol. 83:483–93
     [Google Scholar]
  34. 34. 
    de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C et al. 2010. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133:23–32
     [Google Scholar]
  35. 35. 
    de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y et al. 2017. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49:256–61
     [Google Scholar]
  36. 36. 
    De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI 1991. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N. Engl. J. Med. 325:703–9
     [Google Scholar]
  37. 37. 
    Depienne C, Arzimanoglou A, Trouillard O, Fedirko E, Baulac S et al. 2006. Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy. Hum. Mutat. 27:389
     [Google Scholar]
  38. 38. 
    Devinsky O, Vezzani A, O'Brien TJ, Jette N, Scheffer IE et al. 2018. Epilepsy. Nat. Rev. Dis. Primers 4:18024
     [Google Scholar]
  39. 39. 
    D'Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE et al. 2017. Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep 21:3754–66
     [Google Scholar]
  40. 40. 
    Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL et al. 2013. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat. Genet. 45:546–51
     [Google Scholar]
  41. 41. 
    Dibbens LM, Mullen S, Helbig I, Mefford HC, Bayly MA et al. 2009. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum. Mol. Genet. 18:3626–31
     [Google Scholar]
  42. 42. 
    Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE et al. 2008. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat. Genet. 40:776–81
     [Google Scholar]
  43. 43. 
    Dolzhenko E, van Vugt J, Shaw RJ, Bekritsky MA, van Blitterswijk M et al. 2017. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res 27:1895–903
     [Google Scholar]
  44. 44. 
    Dravet C. 2011. The core Dravet syndrome phenotype. Epilepsia 52:Suppl. 23–9
     [Google Scholar]
  45. 45. 
    Ellis CA, Petrovski S, Berkovic SF 2020. Epilepsy genetics: clinical impacts and biological insights. Lancet Neurol 19:93–100
     [Google Scholar]
  46. 46. 
    Emdin CA, Khera AV, Kathiresan S 2017. Mendelian randomization. JAMA 318:1925–26
     [Google Scholar]
  47. 47. 
    Epi4K Consort 2012. Epi4K: gene discovery in 4,000 genomes. Epilepsia 53:1457–67
     [Google Scholar]
  48. 48. 
    Epi4K Consort 2017. Phenotypic analysis of 303 multiplex families with common epilepsies. Brain 140:2144–56
     [Google Scholar]
  49. 49. 
    Epi4K Consort., Epilepsy Phenome/Genome Proj 2013. De novo mutations in epileptic encephalopathies. Nature 501:217–21
     [Google Scholar]
  50. 50. 
    Epi4K Consort., Epilepsy Phenome/Genome Proj 2017. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol 16:135–43
     [Google Scholar]
  51. 51. 
    Epi25 Collab 2019. Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals. Am. J. Hum. Genet. 105:267–82
     [Google Scholar]
  52. 52. 
    Epicure Consort., EMINet Consort., Steffens M, Leu C, Ruppert AK et al. 2012. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum. Mol. Genet. 21:5359–72
     [Google Scholar]
  53. 53. 
    Eriksson H, Wirdefeldt K, Asberg S, Zelano J 2019. Family history increases the risk of late seizures after stroke. Neurology 93:e1964–70
     [Google Scholar]
  54. 54. 
    Espinosa-Jovel C, Toledano R, Aledo-Serrano A, Garcia-Morales I, Gil-Nagel A 2018. Epidemiological profile of epilepsy in low income populations. Seizure 56:67–72
     [Google Scholar]
  55. 55. 
    Feenstra B, Pasternak B, Geller F, Carstensen L, Wang T et al. 2014. Common variants associated with general and MMR vaccine-related febrile seizures. Nat. Genet. 46:1274–82
     [Google Scholar]
  56. 56. 
    Ferreira MAR, Mathur R, Vonk JM, Szwajda A, Brumpton B et al. 2019. Genetic architectures of childhood- and adult-onset asthma are partly distinct. Am. J. Hum. Genet. 104:665–84
     [Google Scholar]
  57. 57. 
    Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E et al. 2017. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:522–30
     [Google Scholar]
  58. 58. 
    Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P et al. 2005. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–72
     [Google Scholar]
  59. 59. 
    Florian RT, Kraft F, Leitao E, Kaya S, Klebe S et al. 2019. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with familial adult myoclonic epilepsy type 3. Nat. Commun. 10:4919
     [Google Scholar]
  60. 60. 
    Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S et al. 2016. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat. Genet. 48:134–43
     [Google Scholar]
  61. 61. 
    Gilliam F. 2002. Optimizing health outcomes in active epilepsy. Neurology 58:S9–20
     [Google Scholar]
  62. 62. 
    Gormley P, Anttila V, Winsvold BS, Palta P, Esko T et al. 2016. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat. Genet. 48:856–66
     [Google Scholar]
  63. 63. 
    Grinton BE, Heron SE, Pelekanos JT, Zuberi SM, Kivity S et al. 2015. Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome. Epilepsia 56:1071–80
     [Google Scholar]
  64. 64. 
    Hauser WA, Annegers JF, Kurland LT 1993. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 34:453–68
     [Google Scholar]
  65. 65. 
    Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M et al. 2009. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41:160–62
     [Google Scholar]
  66. 66. 
    Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z et al. 2016. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet. Med. 18:898–905
     [Google Scholar]
  67. 67. 
    Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E et al. 2012. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 44:1188–90
     [Google Scholar]
  68. 68. 
    Hesdorffer DC, Logroscino G, Benn EK, Katri N, Cascino G, Hauser WA 2011. Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota. Neurology 76:23–27
     [Google Scholar]
  69. 69. 
    Hildebrand MS, Harvey AS, Malone S, Damiano JA, Do H et al. 2018. Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome. Neurol Genet 4:e236
     [Google Scholar]
  70. 70. 
    Howell KB, Eggers S, Dalziel K, Riseley J, Mandelstam S et al. 2018. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 59:1177–87
     [Google Scholar]
  71. 71. 
    Hwang B, Lee JH, Bang D 2018. Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp. Mol. Med. 50:96
     [Google Scholar]
  72. 72. 
    Int. League Against Epilepsy Consort. Complex Epilepsies 2014. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol 13:893–903
     [Google Scholar]
  73. 73. 
    Int. League Against Epilepsy Consort. Complex Epilepsies 2018. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat. Commun 9:5269
     [Google Scholar]
  74. 74. 
    Int. Mult. Scler. Genet. Consort 2013. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet 45:1353–60
     [Google Scholar]
  75. 75. 
    Ishida S, Picard F, Rudolf G, Noe E, Achaz G et al. 2013. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat. Genet. 45:552–55
     [Google Scholar]
  76. 76. 
    Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK et al. 2018. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat. Genet. 50:581–90
     [Google Scholar]
  77. 77. 
    Jallon P, Latour P. 2005. Epidemiology of idiopathic generalized epilepsies. Epilepsia 46:Suppl. 910–14
     [Google Scholar]
  78. 78. 
    Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J et al. 2014. Somatic mutations in cerebral cortical malformations. N. Engl. J. Med. 371:733–43
     [Google Scholar]
  79. 79. 
    Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C et al. 2018. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat. Genet. 50:1219–24
     [Google Scholar]
  80. 80. 
    Lal D, Reinthaler EM, Schubert J, Muhle H, Riesch E et al. 2014. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann. Neurol. 75:788–92
     [Google Scholar]
  81. 81. 
    Lam M, Hill WD, Trampush JW, Yu J, Knowles E et al. 2019. Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways. Am. J. Hum. Genet. 105:334–50
     [Google Scholar]
  82. 82. 
    Lee JJ, Wedow R, Okbay A, Kong E, Maghzian O et al. 2018. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat. Genet. 50:1112–21
     [Google Scholar]
  83. 83. 
    Lehesjoki AE, Koskiniemi M. 1999. Progressive myoclonus epilepsy of Unverricht-Lundborg type. Epilepsia 40:Suppl. 323–28
     [Google Scholar]
  84. 84. 
    Lei XX, Liu Q, Lu Q, Huang Y, Zhou XQ et al. 2019. TTTCA repeat expansion causes familial cortical myoclonic tremor with epilepsy. Eur. J. Neurol. 26:513–18
     [Google Scholar]
  85. 85. 
    Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M et al. 2013. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat. Genet. 45:1067–72
     [Google Scholar]
  86. 86. 
    Lerche H, Berkovic SF, Lowenstein DH 2019. Intestinal-cell kinase and juvenile myoclonic epilepsy. N. Engl. J. Med 380:e24
     [Google Scholar]
  87. 87. 
    Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A et al. 2013. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat. Genet. 45:1061–66
     [Google Scholar]
  88. 88. 
    Leu C, Stevelink R, Smith AW, Goleva SB, Kanai M et al. 2019. Polygenic burden in focal and generalized epilepsies. Brain 142:3473–81
     [Google Scholar]
  89. 89. 
    Ligthart S, Vaez A, Vosa U, Stathopoulou MG, de Vries PS et al. 2018. Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am. J. Hum. Genet. 103:691–706
     [Google Scholar]
  90. 90. 
    Lim JS, Kim WI, Kang HC, Kim SH, Park AH et al. 2015. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat. Med. 21:395–400
     [Google Scholar]
  91. 91. 
    Luo Y, Hitz BC, Gabdank I, Hilton JA, Kagda MS et al. 2020. New developments on the Encyclopedia of DNA Elements (ENCODE) data portal. Nucleic Acids Res 48:D882–89
     [Google Scholar]
  92. 92. 
    Maljevic S, Møller RS, Reid CA, Pérez-Palma E, Lal D et al. 2019. Spectrum of GABAA receptor variants in epilepsy. Curr. Opin. Neurol. 32:183–90
     [Google Scholar]
  93. 93. 
    Mantegazza M, Gambardella A, Rusconi R, Schiavon E, Annesi F et al. 2005. Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. PNAS 102:18177–82
     [Google Scholar]
  94. 94. 
    Marini C, Scheffer IE, Nabbout R, Suls A, De Jonghe P et al. 2011. The genetics of Dravet syndrome. Epilepsia 52:Suppl. 224–29
     [Google Scholar]
  95. 95. 
    Martin AR, Daly MJ, Robinson EB, Hyman SE, Neale BM 2019. Predicting polygenic risk of psychiatric disorders. Biol. Psychiatry 86:97–109
     [Google Scholar]
  96. 96. 
    Martin MS, Tang B, Papale LA, Yu FH, Catterall WA, Escayg A 2007. The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum. Mol. Genet. 16:2892–99
     [Google Scholar]
  97. 97. 
    May P, Girard S, Harrer M, Bobbili DR, Schubert J et al. 2018. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study. Lancet Neurol 17:699–708
     [Google Scholar]
  98. 98. 
    McClelland AC, Gomes WA, Shinnar S, Hesdorffer DC, Bagiella E et al. 2016. Quantitative evaluation of medial temporal lobe morphology in children with febrile status epilepticus: results of the FEBSTAT study. Am. J. Neuroradiol. 37:2356–62
     [Google Scholar]
  99. 99. 
    McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE 2016. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 15:304–16
     [Google Scholar]
  100. 100. 
    Mefford HC, Muhle H, Ostertag P, von Spiczak S, Buysse K et al. 2010. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLOS Genet 6:e1000962
     [Google Scholar]
  101. 101. 
    Mefford HC, Yendle SC, Hsu C, Cook J, Geraghty E et al. 2011. Rare copy number variants are an important cause of epileptic encephalopathies. Ann. Neurol. 70:974–85
     [Google Scholar]
  102. 102. 
    Michelucci R, Poza JJ, Sofia V, de Feo MR, Binelli S et al. 2003. Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families. Epilepsia 44:1289–97
     [Google Scholar]
  103. 103. 
    Moulard B, Darcel F, Mignard D, Jeanpierre M, Genton P et al. 2003. Founder effect in patients with Unverricht-Lundborg disease on reunion island. Epilepsia 44:1357–60
     [Google Scholar]
  104. 104. 
    Mousavi N, Shleizer-Burko S, Yanicky R, Gymrek M 2019. Profiling the genome-wide landscape of tandem repeat expansions. Nucleic Acids Res 47:e90
     [Google Scholar]
  105. 105. 
    Mullen SA 2018. Genetic generalized epilepsies. Epilepsia 59:1148–53
     [Google Scholar]
  106. 106. 
    Mullen SA, Carvill GL, Bellows S, Bayly MA, Trucks H et al. 2013. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 81:1507–14
     [Google Scholar]
  107. 107. 
    Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD et al. 2012. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2197–223
     [Google Scholar]
  108. 108. 
    Myers CT, Hollingsworth G, Muir AM, Schneider AL, Thuesmunn Z et al. 2018a. Parental mosaicism in “de novo” epileptic encephalopathies. N. Engl. J. Med. 378:1646–48
     [Google Scholar]
  109. 109. 
    Myers KA, Scheffer IE 2018b. Genetic literacy series: genetic epilepsy with febrile seizures plus. Epileptic Disord 20:232–38
     [Google Scholar]
  110. 110. 
    Nashabat M, Al Qahtani XS, Almakdob S, Altwaijri W, Ba-Armah DM et al. 2019. The landscape of early infantile epileptic encephalopathy in a consanguineous population. Seizure 69:154–72
     [Google Scholar]
  111. 111. 
    Nazarian A, Yashin AI, Kulminski AM 2019. Genome-wide analysis of genetic predisposition to Alzheimer's disease and related sex disparities. Alzheimer's Res. Ther. 11:5
     [Google Scholar]
  112. 112. 
    Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F et al. 2018. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97:1268–83.e6
     [Google Scholar]
  113. 113. 
    Niestroj LM, May P, Artomov M, Kobow K, Coras R et al. 2019. Assessment of genetic variant burden in epilepsy-associated brain lesions. Eur. J. Hum. Genet. 27:1738–44
     [Google Scholar]
  114. 114. 
    Ottman R, Risch N, Hauser WA, Pedley TA, Lee JH et al. 1995. Localization of a gene for partial epilepsy to chromosome 10q. Nat. Genet. 10:56–60
     [Google Scholar]
  115. 115. 
    Oyrer J, Maljevic S, Scheffer IE, Berkovic SF, Petrou S, Reid CA 2018. Ion channels in genetic epilepsy: from genes and mechanisms to disease-targeted therapies. Pharmacol. Rev. 70:142–73
     [Google Scholar]
  116. 116. 
    Papuc SM, Abela L, Steindl K, Begemann A, Simmons TL et al. 2019. The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study. Eur. J. Hum. Genet. 27:408–21
     [Google Scholar]
  117. 117. 
    Pelc K, Boyd SG, Cheron G, Dan B 2008. Epilepsy in Angelman syndrome. Seizure 17:211–17
     [Google Scholar]
  118. 118. 
    Peljto AL, Barker-Cummings C, Vasoli VM, Leibson CL, Hauser WA et al. 2014. Familial risk of epilepsy: a population-based study. Brain 137:795–805
     [Google Scholar]
  119. 119. 
    Perucca P. 2018. Genetics of focal epilepsies: What do we know and where are we heading. Epilepsy Curr 18:356–62
     [Google Scholar]
  120. 120. 
    Perucca P, Crompton DE, Bellows ST, McIntosh AM, Kalincik T et al. 2017. Familial mesial temporal lobe epilepsy and the borderland of deja vu. Ann. Neurol. 82:166–76
     [Google Scholar]
  121. 121. 
    Perucca P, Perucca E. 2019. Identifying mutations in epilepsy genes: impact on treatment selection. Epilepsy Res 152:18–30
     [Google Scholar]
  122. 122. 
    Picard F, Makrythanasis P, Navarro V, Ishida S, de Bellescize J et al. 2014. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology 82:2101–6
     [Google Scholar]
  123. 123. 
    Poduri A, Evrony GD, Cai X, Walsh CA 2013. Somatic mutation, genomic variation, and neurological disease. Science 341:1237758
     [Google Scholar]
  124. 124. 
    Pueschel SM, Louis S, McKnight P 1991. Seizure disorders in Down syndrome. Arch. Neurol. 48:318–20
     [Google Scholar]
  125. 125. 
    Reid CA, Kim T, Phillips AM, Low J, Berkovic SF et al. 2013. Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology 80:1003–8
     [Google Scholar]
  126. 126. 
    Ribierre T, Deleuze C, Bacq A, Baldassari S, Marsan E et al. 2018. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J. Clin. Investig. 128:2452–58
     [Google Scholar]
  127. 127. 
    Rich SS, Annegers JF, Hauser WA, Anderson VE 1987. Complex segregation analysis of febrile convulsions. Am. J. Hum. Genet. 41:249–57
     [Google Scholar]
  128. 128. 
    Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS et al. 2016. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann. Neurol. 79:120–31
     [Google Scholar]
  129. 129. 
    Rubboli G, Plazzi G, Picard F, Nobili L, Hirsch E et al. 2019. Mild malformations of cortical development in sleep-related hyper motor epilepsy due to KCNT1 mutations. Ann. Clin. Transl. Neurol. 6:386–91
     [Google Scholar]
  130. 130. 
    Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J et al. 2017. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:512–21
     [Google Scholar]
  131. 131. 
    Scheffer IE, Bhatia KP, Lopes-Cendes I, Fish DR, Marsden CD et al. 1995. Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder. Brain 118:61–73
     [Google Scholar]
  132. 132. 
    Scheffer IE, Heron SE, Regan BM, Mandelstam S, Crompton DE et al. 2014. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann. Neurol. 75:782–87
     [Google Scholar]
  133. 133. 
    Scheffer IE, Phillips HA, O'Brien CE, Saling MM, Wrennall JA et al. 1998. Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann. Neurol. 44:890–99
     [Google Scholar]
  134. 134. 
    Schizophr. Work. Group Psychiatr. Genom. Consort 2014. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–27
     [Google Scholar]
  135. 135. 
    Seidner G, Alvarez MG, Yeh JI, O'Driscoll KR, Klepper J et al. 1998. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat. Genet. 18:188–91
     [Google Scholar]
  136. 136. 
    Shaw M, Winczewska-Wiktor A, Badura-Stronka M, Koirala S, Gardner A et al. 2020. Exome report: novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities. Eur. J. Med. Genet. 63:103799
     [Google Scholar]
  137. 137. 
    Shellhaas RA, Wusthoff CJ, Tsuchida TN, Glass HC, Chu CJ et al. 2017. Profile of neonatal epilepsies: characteristics of a prospective US cohort. Neurology 89:893–99
     [Google Scholar]
  138. 138. 
    Shinnar S, Glauser TA. 2002. Febrile seizures. J. Child Neurol. 17:Suppl. 1S44–52
     [Google Scholar]
  139. 139. 
    Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP et al. 2013. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N. Engl. J. Med 368:1971–79
     [Google Scholar]
  140. 140. 
    Sim NS, Ko A, Kim WK, Kim SH, Kim JS et al. 2019. Precise detection of low-level somatic mutation in resected epilepsy brain tissue. Acta Neuropathol 138:901–12
     [Google Scholar]
  141. 141. 
    Sim NS, Seo Y, Lim JS, Kim WK, Son H et al. 2018. Brain somatic mutations in SLC35A2 cause intractable epilepsy with aberrant N-glycosylation. Neurol. Genet. 4:e294
     [Google Scholar]
  142. 142. 
    Speed D, Balding DJ. 2019. SumHer better estimates the SNP heritability of complex traits from summary statistics. Nat. Genet. 51:277–84
     [Google Scholar]
  143. 143. 
    Steel D, Symonds JD, Zuberi SM, Brunklaus A 2017. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia 58:1807–16
     [Google Scholar]
  144. 144. 
    Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA et al. 1995. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 11:201–3
     [Google Scholar]
  145. 145. 
    Strehlow V, Heyne HO, Vlaskamp DRM, Marwick KFM, Rudolf G et al. 2019. GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain 142:80–92
     [Google Scholar]
  146. 146. 
    Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM et al. 2002. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat. Genet. 30:441–45
     [Google Scholar]
  147. 147. 
    Suls A, Dedeken P, Goffin K, Van Esch H, Dupont P et al. 2008. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 131:1831–44
     [Google Scholar]
  148. 148. 
    Suls A, Mullen SA, Weber YG, Verhaert K, Ceulemans B et al. 2009. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann. Neurol. 66:415–19
     [Google Scholar]
  149. 149. 
    Takata A, Nakashima M, Saitsu H, Mizuguchi T, Mitsuhashi S et al. 2019. Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy. Nat. Commun. 10:2506
     [Google Scholar]
  150. 150. 
    Tang H, Kirkness EF, Lippert C, Biggs WH, Fabani M et al. 2017. Profiling of short-tandem-repeat disease alleles in 12,632 human whole genomes. Am. J. Hum. Genet. 101:700–15
     [Google Scholar]
  151. 151. 
    Tankard RM, Bennett MF, Degorski P, Delatycki MB, Lockhart PJ, Bahlo M 2018. Detecting expansions of tandem repeats in cohorts sequenced with short-read sequencing data. Am. J. Hum. Genet. 103:858–73
     [Google Scholar]
  152. 152. 
    Thomas RH, Berkovic SF. 2014. The hidden genetics of epilepsy—a clinically important new paradigm. Nat. Rev. Neurol. 10:283–92
     [Google Scholar]
  153. 153. 
    Tinuper P, Bisulli F, Cross JH, Hesdorffer D, Kahane P et al. 2016. Definition and diagnostic criteria of sleep-related hyper motor epilepsy. Neurology 86:1834–42
     [Google Scholar]
  154. 154. 
    Turley P, Walters RK, Maghzian O, Okbay A, Lee JJ et al. 2018. Multi-trait analysis of genome-wide association summary statistics using MTAG. Nat. Genet. 50:229–37
     [Google Scholar]
  155. 155. 
    Vadlamudi L, Milne RL, Lawrence K, Heron SE, Eckhaus J et al. 2014. Genetics of epilepsy: the testimony of twins in the molecular era. Neurology 83:1042–48
     [Google Scholar]
  156. 156. 
    Verity CM, Butler NR, Golding J 1985. Febrile convulsions in a national cohort followed up from birth. I—Prevalence and recurrence in the first five years of life. Br. Med. J. (Clin. Res. Ed.) 290:1307–10
     [Google Scholar]
  157. 157. 
    Wainberg M, Sinnott-Armstrong N, Mancuso N, Barbeira AN, Knowles DA et al. 2019. Opportunities and challenges for transcriptome-wide association studies. Nat. Genet. 51:592–99
     [Google Scholar]
  158. 158. 
    Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN et al. 2001. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat. Genet. 28:49–52
     [Google Scholar]
  159. 159. 
    Willer CJ, Li Y, Abecasis GR 2010. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–91
     [Google Scholar]
  160. 160. 
    Winawer MR, Griffin NG, Samanamud J, Baugh EH, Rathakrishnan D et al. 2018. Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann. Neurol. 83:1133–46
     [Google Scholar]
  161. 161. 
    Xue A, Wu Y, Zhu Z, Zhang F, Kemper KE et al. 2018. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat. Commun. 9:2941
     [Google Scholar]
  162. 162. 
    Ye Z, McQuillan L, Poduri A, Green TE, Matsumoto N et al. 2019. Somatic mutation: the hidden genetics of brain malformations and focal epilepsies. Epilepsy Res 155:106161
     [Google Scholar]
  163. 163. 
    Yeetong P, Pongpanich M, Srichomthong C, Assawapitaksakul A, Shotelersuk V et al. 2019. TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4. Brain 142:3360–66
     [Google Scholar]
  164. 164. 
    Young AI. 2019. Solving the missing heritability problem. PLOS Genet 15:e1008222
     [Google Scholar]
  165. 165. 
    Zhang YH, Burgess R, Malone JP, Glubb GC, Helbig KL et al. 2017. Genetic epilepsy with febrile seizures plus: refining the spectrum. Neurology 89:1210–19
     [Google Scholar]
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The Genetics of Epilepsy
Annual Review of Genomics and Human Genetics 21, 205 (2020); https://doi.org/10.1146/annurev-genom-120219-074937
/content/journals/10.1146/annurev-genom-120219-074937
/content/journals/10.1146/annurev-genom-120219-074937
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